There are important contributions to risk for drug addiction by both genetic and environmental factors. Genome-wide association studies (GWAS) of complex diseases, including drug addiction, have begun to yield successes. Under this existing data program announcement, we propose a Post-GWAS analysis of initiation, dependence and cessation of alcohol, tobacco and illicit drugs in a population- based sample composed of 3 largely African-American cohorts ascertained in Baltimore, Maryland and followed intensively from childhood through young adulthood. We use the term 'Post-GWAS' to describe an analytic plan that derives objective hypotheses from innovative meta-analyses of publicly available GWAS data. This Post-GWAS study of drug use trajectories takes advantage of genetic, environmental, and developmental phenotypic data in 3 cohorts ascertained by the Johns Hopkins Prevention Intervention Research Center (PIRC). The goal of the PIRC research, commencing in 1985, is to examine the role of individual, social and neighborhood-level factors on developmental transitions in drug use in a largely African Americans sample followed from 1st grade into adulthood. The proposed work is innovative in that our Post-GWAS approach will use information extracted from existing, publicly-available GWAS of drug abuse-related traits to generate genetic hypotheses. This formal synthesis will be accomplished via meta-analysis, leading to a small set (N~500) of risk SNPs, genes, and profile scores for inclusion in subsequent analyses in the PIRC Cohorts. A second unusual aspect is the plan for a systematic scan of the influence of individual and environmental factors on three important aspects of the developmental trajectory of drug use and dependence-- initiation, dependence, and cessation-on three distinct substances: alcohol, tobacco and illicit drugs. The intensive follow-ups of the first graders over decades include a wide range of environmental factors, measured on a host of objective and self-reported indicators. A third innovative aspect is the plan to carry these two risk domains-- Post-GWAS genetic risk factors and PIRC-specific individual and environmental risk factors-- into longitudinal modeling of drug use trajectories. Our approach will investigate both drug-specific and common (general liability) effects as well as the moderating or mediating effects of the environment. The research is significant because the results will identify etiologic pathways in African Americans that will elucidate our understanding of drug use disorders and lead to enhanced efforts at treatment and prevention. Findings from this innovative and cost-effective project could have a significant impact on the creation of developmentally-appropriate, community-wide prevention programs targeted at urban-dwelling African Americans.